Understanding selectivity in signal transduction is one of the most challenging tasks in current cell biology. Over the years, insulin signaling has served as one of the model examples in hormone-induced signal transduction. Complete loss of either insulin or Insulin Receptors (IRs) is lethal. Malfunction of insulin signaling, referred to as insulin resistance, is one of the major causes of type II diabetes (type 2 diabetes mellitus, non-insulin-dependent diabetes mellitus, NIDDM), the most common metabolic disorder in man. Insulin has been shown to exhibit pleiotropic effects, involving mitogenic and/or metabolic events. Moreover, the effect of insulin is tissue- as well as development-dependent. The fact that insulin may transduce its signal through a variety of pathways has been discussed in extensive detail (White and Kahn, 1994). The three major pathways described to date, which employ Insulin Receptors (IRs) as the primary target, include signaling via mitogen activated protein (MAP) kinases, phosphoinositol-3 kinase (PI3K) and phospholipase C. The Insulin Receptor, the first step in these cascades, as a result of alternative mRNA splicing of the 11th exon of the (prepro)Insulin Receptor transcript, exists in two isoforms. The A type, or Ex11− (Ullrich et al., 1985), lacks, whereas the B type, or Ex11+ (Ebina et al., 1985), contains the respective sequence coding for 12 amino acids in the C-terminus of the α-chain of the receptor. To date, no insulin-induced effect has been reported that discriminates signaling via A and B type receptors. In fact, the functional significance of these Insulin Receptor (IR) isoforms remains unclear (for a review see Flier et al 1996). Recent studies have shown that also the insulin-producing pancreatic beta cell is a target for insulin action, with insulin effects on transcription, translation, ion flux and exocytosis of insulin (Leibiger et al., 1998a; Kulkarni et al., 1999; Leibiger et al., 2000). In an animal model with a beta cell-specific knockout for Insulin Receptors, a decrease in glucose stimulated insulin release has been shown and a decrease in the insulin content of the cell (Kulkarni et al., 1999). In addition, disruption of insulin signaling in the beta cell at the level of Insulin Receptor substrate-1 or Insulin Receptor substrate-2 leads to altered growth and function of the beta cell. Consequently, insulin resistance, one of the major causes of type II diabetes may not only affect the function of the ‘classical’ insulin target tissues; muscle, fat and liver, but also apply to the pancreatic beta cell and therefore may affect beta cell function.